Altered RNA editing and malignant progression in oral squamous carcinoma.

• Project/Area Number: 15K11265
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Health Sciences University of Hokkaido
• Principal Investigator: Okumura Kazuhiko 北海道医療大学, 歯学部, 教授 (60194510)
• Co-Investigator(Kenkyū-buntansha): 磯貝 恵美子 東北大学, 農学研究科, 教授 (80113570)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: エピジェネティク / ADAR1 / AZIN1 / FLNB / 口腔扁平上皮癌 / RNA編集異常 / FNLB / 癌の悪性化進展 / ADAR1遺伝子 / レンチウイルスベクター / 造腫瘍活性 / 細胞増殖活性 / 細胞遊走能 / 基底膜浸潤能 / ADAR2 / 癌細胞浸潤能

Outline of Final Research Achievements

Recently, adenosine (A)-to-inosine (I) RNA editing, as it is catalyzed by adenosine deaminases on acting on RNA (ADAR) has been shown to be a potential epigenetic event in human cancers. Here we investigated that role of RNA editing enzyme ADARs and altered RNA editing in oral squamous carcinoma (OSCC) malignant progression. Among the three ADAR enzymes expressed in human cells, only ADAR1was expressed in OSCC cells. We used to modulate the expression of ADAR1 by overexpressing, or silencing ADAR1 reinstating a specific altered edited transcript. As a result of the overexpression of ADAR1in OSCC cells, led to the increased editing frequencies of antizyme inhibitor 1 (AZIN1) and filamin B (FLNB) transcripts. Consistently, silencing ADAR1 by shRNA targeting ADAR1 gene in OSCC cells resulted in the reduced editing level of AZIN1 and FLNB.
These results suggest that the upregulation of ADAR1 in OSCC contributes to the gene specific altered editing pattern.

Academic Significance and Societal Importance of the Research Achievements

A-to-I編集を担うADARsが、ヒトの癌における潜在的なエピジェネティクな変化に関与していることが示されている。そこで、我々は悪性化進展におけるRNA編集酵素ADARとADARによるRNA編集異常の役割について検討した。その結果、口腔扁平上皮癌ではADAR1の過剰発現によってAZIN1とFLNBに編集異常を起こし、悪性化進展を促進していることが示された。これらの結果から、ADARの異常発現が RNA 編集異常の頻度を高め悪性化進展に関与することを示した。
本研究によって、RNA編集異常を標的とした診断法や治療法の開発に向けての基盤研究が確立できると考えられる。

Research Products

• [Journal Article] Regulation of radiosensitivity by 4-methylumbelliferone via the suppression of interleukin-1 in fibrosarcoma cells (2019)
  • Author(s): Saga R, Hasegawa K, Murata K, Chiba M, Nakamura T, Okumura K, Tsuruga E, Hosokawa Y.
  • Journal Title: Oncology Letters Volume: 17 Pages: 3555-3561
  • DOI: 10.3892/ol.2019.9990
  • Peer Reviewed / Open Access
• [Journal Article] miR-663a regulates growth of colon cancer cells, after administration of antimicrobial peptides, by targeting CXCR4-p21 pathway (2017)
  • Author(s): Kuroda K, Fukuda T, Krstic-Demonacos M, Demonacos C, Okumura K, Isogai H, Hayashi M, Saito K, Isogai E
  • Journal Title: BMC Cancer Volume: Jan 7;17(1):33 Issue: 1 Pages: 33-33
  • DOI: 10.1186/s12885-016-3003-9
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The human cathelicidin antimicrobial peptide LL-37 and mimics are potential anticancer drugs. (2015)
  • Author(s): Kuroda, K., OKumura, K., Isogai, H., Isogai, E.
  • Journal Title: Front Oncol Volume: 5 Pages: 1-10
  • DOI: 10.3389/fonc.2015.00144
  • Peer Reviewed / Open Access